c-Myc augments the apoptotic activity of cytosolic death receptor signaling proteins by engaging the mitochondrial apoptotic pathway
c-Myc augments the apoptotic activity of cytosolic death receptor signaling proteins by engaging the mitochondrial apoptotic pathway
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DOI：
10.1074/jbc.m206967200
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发表时间：
2002-11-08
影响因子：
4.8
通讯作者：
Evan, G
中科院分区：
文献类型：
--
作者：
Klefstrom, J;Verschuren, EW;Evan, G
c-Myc的激活使细胞对配体激活的死亡受体诱导的凋亡敏感。癌基因对死亡受体的这种敏感性很可能是肿瘤细胞对肿瘤坏死因子（TNF）或TNF相关凋亡诱导配体（TRAIL）敏感性的机制。这种c-Myc诱导的致敏发生的机制尚不清楚，但可能涉及死亡受体或其配体表达的调节或线粒体释放促凋亡效应物如全细胞色素c的敏感性增强。在这里，我们表明，异位表达的死亡受体信号蛋白RIP（受体相互作用蛋白）触发细胞凋亡通过FAS相关的死亡结构域蛋白（FADD）和caspase 8依赖的途径。通过c-Myc表达显著增强通过死亡受体信号传导途径的这种细胞内活化诱导的细胞凋亡。此外，c-Myc表达强烈促进RIP诱导细胞色素c从线粒体释放的潜力。这暗示了线粒体凋亡途径在这种协同作用中，这一概念通过c-Myc不能在缺乏专性线粒体凋亡效应物Bax和巴克的细胞中对RIP杀伤敏感而得到证实。我们得出结论，RIP激活的胞质caspase 8通路的致死性增加了c-Myc启动线粒体释放细胞色素c。这将c-Myc和死亡受体信号传导之间的凋亡协同作用的交叉点置于死亡受体的下游。
Activation of c-Myc sensitizes cells to apoptosis induction by ligand-activated death receptors. Such sensitization to death receptors by oncogenes may well be the mechanism underlying tumor cell sensitivity to tumor necrosis factor (TNF) or TNF-related apoptosis-inducing ligand (TRAIL). The mechanism by which this c-Myc-induced sensitization occurs is unclear but could involve modulation of expression of death receptors or their ligands or potentiation of the sensitivity of mitochondria to release pro-apoptotic effectors such as holocytochrome c. Here, we show that ectopic expression of the death receptor signaling protein RIP (receptor-interactive protein) triggers apoptosis via a FAS-associated death domain protein (FADD) and caspase 8-dependent pathway. Induction of apoptosis by this intracellular activation of the death receptor signaling pathway is significantly augmented by c-Myc expression. Moreover, c-Myc expression strongly promotes the potential of RIP to induce cytochrome c release from mitochondria. This implicates the mitochondrial apoptotic pathway in this synergy, a notion confirmed by the inability of c-Myc to sensitize to RIP killing in cells lacking the obligate mitochondrial apoptotic effectors Bax and Bak. We conclude that the lethality of the RIP-activated cytosolic caspase 8 pathway is augmented by c-Myc priming mitochondria to release cytochrome c. This places the intersection of apoptotic synergy between c-Myc and death receptor signaling downstream of the death receptors.